GART INHIBITION ENHANCES THE EFFICACY OF MEK INHIBITOR IN KRAS- OR BRAF-DRIVEN CANCERS

MEK inhibitor such as AZD6244 (selumetinib) targets the MAPK/ERK pathway by allosterically inhibiting MEK1/2 and have received clinical approval for BRAF V600E- mutant melanoma and are under study in KRAS/BRAF-mutant tumors. However, single- agent MEK inhibition often shows limited clinical responses in KRAS-driven cancers, with frequent intrinsic or acquired resistance leading to continued tumor proliferation. In KRAS mutant contexts, robust pathway reactivation and metabolic rewiring can sustain growth despite MEK blockade. Furthermore, oncogenic drivers such as c-MYC orchestrate broad metabolic programs essential for biomass production and energy supply, which are not fully suppressed by MEK inhibition alone. Some recent data indicate that low doses of the GART inhibitor AG2037 reduce mTORC1 activity, consistent with a response to purine depletion. In this project, we also found that AG2037 and the MEK inhibitor AZD6244 act synergistically, leading to a stronger suppression of KRAS- and BRAF-driven tumor cell growth. The decrease in c-MYC observed with the combination treatment is likely linked to reduced mTORC1 signaling. Together, these findings suggest that GART inhibition can improve the response to MEK inhibitor by dampening mTORC1 activity and lowering c- MYC levels.